Mycothiol Associated Genes in ROI and RNI Stress Response

ROI 和 RNI 应激反应中的菌硫醇相关基因

• 批准号: 7486139
• 负责人: MAMTA RAWAT
• 金额: $ 9.04万
• 依托单位: CALIFORNIA STATE UNIVERSITY FRESNO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7486139
• 关键词: Actinobacteria class; Actinomyces; Actinomycetales; Animal Model; BCG Vaccine; Biochemical; Biological Assay; Calmette-Guerin Bacillus; Caring; Cause of Death; Cell Survival; Cells; Cloning; Code; Containment; Diagnosis; Disease; Disulfides; Drug Delivery Systems; Environment; Enzyme Gene; Enzymes; Genes; Genus Mycobacterium; Granuloma; HIV Infections; Homelessness; Human; Immune system; Immunocompromised Host; Individual; Libraries; Medical; Metabolism; Molecular Weight; Multi-Drug Resistance; Mutagenesis; Mycobacterium bovis; Mycobacterium tuberculosis; Nitrogen; Organism; Oxidative Stress; Oxidoreductase; Oxygen; Pathogenesis; Peroxidase; Peroxidases; Phagosomes; Pharmacotherapy; Population; Production; Proteins; Public Health; Rate; Recombinant Proteins; Reducing Agents; Research Proposals; Risk; Role; Screening procedure; Stress; Sulfhydryl Compounds; Testing; Transferase; Tuberculosis; Virulence Factors; biological adaptation to stress; cofactor; gene function; glutaredoxin; glutathione analog; interest; killings; macrophage; microbial; microorganism; mutant; mycobacterial; mycothiol; novel; peroxiredoxin; repaired

Tuberculosis (TB) is the leading cause of death among microbial agents in the world killing two million people annually. One-third of the world population is infected with Mycobacterium tuberculosis, the causative agent of the disease tuberculosis (TB). Immunocompromised individuals such as those diagnosed with HIV infections and the homeless who do not have access to medical care are at a greater risk for developing TB. In addiiton, although drug therapy for TB is available, compliance rates are low and have resulted in the emergence of multi-drug resistant strains. For these reasons, TB is again a public health threat and there is a renewal of scientific interest in the identification of virulence factors that aid in the pathogenesis of this organism. Mycobacterium tuberculosis is a facultative intracellular organism that resides and replicates within the macrophages of the host immune system. One of the ways the macrophage kills microorganisms is by releasing reactive oxygen and nitrogen species that are harmful to the microorganism. In this research proposal, genes coding for such enzymes as peroxiredoxins, glutaredoxin like "mycoredoxins", and nitrosothiol reductase that protect against oxidative and nitrosative stress and therefore aid in the survival of mycobacteria in macrophages will be investigated. In particular, enzymes requiring mycothiol, a unique thiol that is present exclusively in Actinomycetes and is essential to the mycobacterial cell, will be studied. M bovis BCG targeted mutants will be created in genes that encode these mycothiol dependent genes to validate gene function and to determine the role of these genes in pathogenesis. A transposon mutant library of M. bovis BCG will also be created and screened for mutants sensitive to disulfide stress which would result in the depletion of thiols in the cell. Mycobacterium bovis BCG, the vaccine strain for M. tuberculosis, is a model organism for studying M. tuberculosis virulence factors in Biosafety Level 2 containment.

结核病 (TB) 是世界上微生物死亡的主要原因，导致 200 万人死亡 人每年。世界上三分之一的人口感染了结核分枝杆菌， 结核病 (TB) 的病原体。免疫功能低下的个体，例如被诊断出的个体 艾滋病毒感染者和无法获得医疗服务的无家可归者面临更大的感染风险 正在发展结核病。此外，尽管可以进行结核病药物治疗，但依从率很低，并且 导致多重耐药菌株的出现。由于这些原因，结核病再次成为一种公共卫生问题 威胁，科学界对识别毒力因子重新产生了兴趣，这些毒力因子有助于 该生物体的发病机制。 结核分枝杆菌是一种兼性细胞内生物，在细胞内驻留和复制。 宿主免疫系统的巨噬细胞。巨噬细胞杀死微生物的方式之一是 释放对微生物有害的活性氧和氮。在这项研究中 提案，编码过氧化还蛋白、谷氧还蛋白如“真菌还蛋白”等酶的基因，以及 亚硝基硫醇还原酶可防止氧化和亚硝化应激，从而有助于生存 将研究巨噬细胞中的分枝杆菌。特别是需要菌硫醇（一种独特的硫醇）的酶 将研究仅存在于放线菌中并且对分枝杆菌细胞至关重要的物质。中号 牛 BCG 靶向突变体将在编码这些菌硫醇依赖性基因的基因中产生，以 验证基因功能并确定这些基因在发病机制中的作用。转座子突变体库 牛支原体 BCG 也将被创建并筛选对二硫键胁迫敏感的突变体，这将 导致细胞内硫醇的耗尽。牛分枝杆菌 BCG，结核分枝杆菌的疫苗株， 是用于研究生物安全 2 级遏制中结核分枝杆菌毒力因子的模型生物。